Multi-polymer compositions for transdermal drug delivery

ABSTRACT

Multi-polymer compositions for the transdermal delivery of drugs, such as amine-functional drugs, in a flexible, finite form are described. The compositions comprise a polymer matrix that includes a drug or a pharmaceutically acceptable salt thereof and a polymer matrix comprising acrylic polymer(s), polyisobutylene polymer(s) and styrene-isoprene-styrene block copolymer(s). Methods of manufacturing and methods of using the compositions also are described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 USC §119(e) to U.S.provisional application 61/747,117, filed Dec. 28, 2012, the entirecontents of which are incorporated herein by reference in theirentirety.

FIELD

Described here are multi-polymer compositions for transdermal drugdelivery, methods of making them, and methods of effecting transdermaldrug delivery using them. In some embodiments, the drug is anamine-functional drug, such as clonidine.

BACKGROUND

Many factors influence the design and performance of transdermal drugdelivery compositions. These include the individual drugs themselves,the physical and chemical characteristics of the compositions'components and their performance and behavior relative to othercomponents, external and environmental conditions during manufacturingand storage, properties of the application site, the desired rate ofdrug delivery and therapeutic onset, the desired drug delivery profile,and the intended duration of delivery, among others.

Compositions for the transdermal delivery of amine-functional drugs areknown, but there remains a need for compositions that exhibit suitablephysical and pharmacokinetic properties. Further, there remains a needfor compositions that can provide drug delivery over a period of time ofabout 24 hours, or that can provide drug delivery over an extendedperiod of time, such as a period of about 7 days.

SUMMARY

In accordance with some embodiments, there are provided multi-polymercompositions for the transdermal delivery of an amine-functional drug inthe form of a flexible finite system for topical application, comprisinga polymer matrix comprising (i) a therapeutically effective amount of anamine-functional drug; (ii) an acrylic polymer; (iii) a polyisobutylenepolymer, and (iv) a styrene-isoprene-styrene block copolymer. Inspecific embodiments, the amine-functional drug comprises clonidine, andthe polymer matrix may comprise about 1% to 10% clonidine.

In some embodiments, the polymer matrix comprises two or more acrylicpolymers. In any embodiments, the polymer matrix may comprise a nonacid-functional acrylic polymer. In any embodiments, the polymer matrixmay comprise about 85% to 95% w/w acrylic polymer. In any embodiments,the polymer matrix may comprise about 3% to 5% w/w polyisobutylenepolymer. In any embodiments, the polymer matrix may comprise about 1% to2% w/w styrene-isoprene-styrene block copolymer.

In any embodiments, the polymer matrix may have a coat weight of about10 to 15 mg/cm².

In some embodiments, the system achieves delivery of theamine-functional drug over a period of time of about 24 hours. In otherembodiments, the system achieves delivery of the amine-functional drugover a period of time of about 7 days.

In any embodiments, the system further comprises a backing layer and/ora release liner.

Also provided are methods for the transdermal delivery of anamine-functional drug, comprising topically applying a composition asdescribed herein to the skin or mucosa of a subject in need thereof.

Also provided are methods for the manufacture of a composition asdescribed herein, comprising:

optionally, drying one or more of an acrylic polymer, a polyisobutylenepolymer, and a styrene-isoprene-styrene block copolymer to remove anysolvent;

dissolving an acrylic polymer, a polyisobutylene polymer, and astyrene-isoprene-styrene block copolymer in a solvent miscible with theamine-functional drug and polymer components and mixing to form apolymer blend;

adding the amine-functional drug to the polymer blend and mixing to forma polymer matrix;

applying the polymer matrix to a release liner;

removing solvent from the polymer matrix; and

providing the polymer matrix with a backing layer.

In specific embodiments, the amine-functional drug is clonidine and thesolvent is toluene.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the results of in vitro drug flux studies of clonidine froma 1 day mutli-polymer system described herein (▪) as compared to thecommercially available Catapres-TTS® transdermal clonidine patch (♦).

FIG. 2 shows the results of in vitro drug flux studies of clonidine froma 7 day mutli-polymer system described herein (▴, , -×-) as compared tothe commercially available Catapres-TTS® transdermal clonidine patch(♦).

DETAILED DESCRIPTION

Described herein are multi-polymer compositions, methods of making them,and methods for effecting the transdermal delivery of a drug, such as anamine-functional drug, using them. The compositions are provided in aflexible, finite form (e.g., “patch”-type systems) that comprise apolymer matrix that includes a drug or a pharmaceutically acceptablesalt thereof, and that also is provided with a backing layer. Thecompositions exhibit satisfactory physical properties while alsoachieving satisfactory pharmacokinetic profiles. In specificembodiments, the polymer matrix comprises (i) a therapeuticallyeffective amount of an amine-functional drug or pharmaceuticallyacceptable salt thereof; (ii) one or more acrylic polymer(s); (iii) oneor more polyisobutylene polymers, and (iv) one or morestyrene-isoprene-styrene block copolymers. In accordance with anyembodiments, the polymer matrix may further comprise one or morepenetration enhancers, and other excipients conventionally used inpolymer matrix-type transdermal drug delivery compositions.

Definitions

Technical and scientific terms used herein have the meanings commonlyunderstood by one of ordinary skill in the art to which the presentinvention pertains, unless otherwise defined. Reference is made hereinto various methodologies known to those of ordinary skill in the art.Publications and other materials setting forth such known methodologiesto which reference is made are incorporated herein by reference in theirentireties as though set forth in full. Any suitable materials and/ormethods known to those of ordinary skill in the art can be utilized incarrying out the present invention. However, specific materials andmethods are described. Materials, reagents and the like to whichreference is made in the following description and examples areobtainable from commercial sources, unless otherwise noted.

As used herein, the singular forms “a,” “an,” and “the” designate boththe singular and the plural, unless expressly stated to designate thesingular only.

The term “about” and the use of ranges in general, whether or notqualified by the term about, means that the number comprehended is notlimited to the exact number set forth herein, and is intended to referto ranges substantially within the quoted range while not departing fromthe scope of the invention. As used herein, “about” will be understoodby persons of ordinary skill in the art and will vary to some extent onthe context in which it is used. If there are uses of the term which arenot clear to persons of ordinary skill in the art given the context inwhich it is used, “about” will mean up to plus or minus 10% of theparticular term.

The phrase “substantially free of” as used herein means that thedescribed composition (e.g., polymer matrix, etc.) comprises less thanabout 5%, less than about 3%, or less than about 1% by weight, based onthe total weight of the composition at issue, of the excludedcomponent(s). The phrase “free of” as used herein means that thedescribed composition (e.g., polymer matrix, etc.) is formulated withoutadding the excluded component(s) as an intended component, althoughtrace amounts may be present in other components or as a by-product orcontaminant, such that the composition comprises at most only traceamounts of the excluded component(s).

As used herein “subject” denotes any mammal in need of drug therapy,including humans. For example, a subject may be suffering from or atrisk of developing a condition that can be treated or prevented with anamine-functional drug, or may be taking an amine-functional drug forother purposes.

As used herein, the terms “topical” and “topically” mean application toa skin or mucosal surface of a mammal, while the terms “transdermal” and“transdermal” connote passage through the skin or mucosa (includingoral, buccal, nasal, rectal and vaginal mucosa), into systemiccirculation. Thus, the compositions described herein may be appliedtopically to a subject to achieve transdermal delivery of anamine-functional drug.

As used herein, the phrases “therapeutically effective amount” and“therapeutic level” mean that drug dosage or plasma concentration in asubject, respectively, that provides the specific pharmacological effectfor which the drug is administered in a subject in need of suchtreatment. It is emphasized that a therapeutically effective amount ortherapeutic level of a drug will not always be effective in treating theconditions/diseases described herein, even though such dosage is deemedto be a therapeutically effective amount by those of skill in the art.For convenience only, exemplary dosages, drug delivery amounts,therapeutically effective amounts and therapeutic levels are providedbelow with reference to adult human subjects. Those skilled in the artcan adjust such amounts in accordance with standard practices as neededto treat a specific subject and/or condition/disease.

The compositions described herein are in a “flexible, finite form.” Asused herein, the phrase “flexible, finite form” means a substantiallysolid form capable of conforming to a surface with which it comes intocontact, and capable of maintaining contact so as to facilitate topicalapplication. Such systems in general are known in the art andcommercially available, such as transdermal drug delivery patches.

The compositions comprise a drug-containing polymer matrix that releasesthe drug upon application to the skin (or any other surface notedabove). The compositions in flexible, finite form also include a backinglayer in addition to the drug-containing polymer matrix layer. In someembodiments, the compositions in flexible, finite form may include arelease liner layer in addition to a drug-containing polymer matrixlayer and backing layer.

As used herein, “drug-containing polymer matrix” refers to a polymercomposition which contains one or more drugs or pharmaceuticallyacceptable salt thereof and a polymer, such as a pressure-sensitiveadhesive polymer or a bioadhesive polymer. A polymer is an “adhesive” or“bioadhesive” if it has the properties of adhesiveness per se. Otherpolymers can function as an adhesive or bioadhesive by the addition oftackifiers, plasticizers, crosslinking agents or other excipients. Thus,in some embodiments, the polymer optionally comprises tackifiers,plasticizers, crosslinking agents or other additives known in the art.

As used herein, the term “pressure-sensitive adhesive” refers to aviscoelastic material which adheres instantaneously to most substrateswith the application of very slight pressure and remains permanentlytacky. As noted above, a polymer is a pressure-sensitive adhesivepolymer if it has the properties of a pressure-sensitive adhesive perse. Other polymers may function as a pressure-sensitive adhesive byadmixture with tackifiers, plasticizers or other additives. The termpressure-sensitive adhesive also includes mixtures of differentpolymers.

In some embodiments, the polymer matrix is a pressure-sensitive adhesiveat room temperature and exhibits desirable physical properties, such asgood adherence to skin, ability to be peeled or otherwise removedwithout substantial trauma to the skin, retention of tack with aging,etc. In some embodiments, the polymer matrix has a glass transitiontemperature (T_(g)), measured using a differential scanning calorimeter,of between about −70 ° C. and 0 ° C.

In some embodiments, the compositions in flexible, finite form are“monolithic” or “monolayer” systems, such that the drug-containingpolymer matrix layer is the only polymeric layer present other than thebacking layer and the release liner, if present. In such embodiments,the polymer matrix functions as both the drug carrier and the means ofaffixing the system to the skin or mucosa.

Polymer Matrix

In accordance with some embodiments, the compositions described hereincomprise a polymer matrix that comprises, consists essentially of, orconsists of, one or more drugs and/or pharmaceutically acceptablesalt(s) thereof and acrylic polymer(s), polyisobutylene polymer(s), andstyrene-isoprene-styrene block copolymer(s). In this context, the phrase“consists essentially of” means that the polymer matrix is substantiallyfree of other polymer components (e.g., substantially free of polymersother than acrylic polymer(s), polyisobutylene polymer(s), andstyrene-isoprene-styrene block copolymer(s)) and skin penetrationenhancers, although it may include other excipients known to be usefulin transdermal compositions (such as tackifiers, plasticizers,crosslinking agents or other excipients known in the art) as long asthose other excipients do not degrade the physical and/orpharmacokinetic properties of the compositions to pharmaceuticallyunacceptable levels. In accordance with some embodiments, thecompositions described herein comprise a polymer matrix that comprises,consists essentially of, or consists of; one or more drugs and/orpharmaceutically acceptable salt(s) thereof and acrylic polymer(s),polyisobutylene polymer(s), and styrene-isoprene-styrene blockcopolymer(s), and, optionally, one or more skin penetration enhacers. Insome embodiments, the compositions described herein are free of or aresubstantially free of silicone polymer(s).

Amine-Functional Drugs

Although the compositions described herein may be useful for anydrug(s), in accordance with some embodiments the compositions compriseone or more amine-functional drugs. The term “amine-functional” denotesa drug or active agent that contains one or more primary amine radicalssuch as phenylpropanolamine, secondary amine radicals such aspropranolol, tertiary amine radicals such as theophylline andchlorpheniramine. The term “amine-functional” also includes heterocyclicamine radicals such as those found in theophylline anddiethylcarbomazine and salts of amine-functional drugs such asscopolamine hydrobromide provided that they can be deliveredtransdermally, but does not include oxidized nitrogen radicals such asnitro radicals. Other examples of amine-functional drugs for transdermaldrug delivery include, for example, tetracain, ephedrine, clonidine,nicotine, ramipril, enalapril, fentanyl and analogs such as alfentanyl,carfentanyl, lofentanyl, remifentanyl, sufentanyl, and trefentanyl,amphetamine, dextroamphetamine, methamphetamine, and atropine. Furtherexamples of amine-functional drugs for use in transdermal drug deliverysystems will be apparent to those skilled in the art. In specificembodiments, the compositions comprise clonidine. In further specificembodiments, the compositions comprise clonidine as the only drugcomponent.

Drug concentration for use according to the present invention is drugdependent, but typically is below about 20% by dry weight of thecomposition, and often is below 10%.

The compositions described herein may be formulated with a drug in itsfree base form, or as any pharmaceutically acceptable salt or esterthereof, or any combinations thereof. Exemplary suitablepharmaceutically acceptable salts are salts of weak inorganic andorganic acids, and quaternary ammonium salts. These include withoutlimitation, salts with acids such as sulfuric, phosphoric, hydrochloric,hydrobromic, hydriodic, sulfamic, citric, lactic, maleic, malic,succinic, tartaric, cinnamic, acetic, benzoic, gluconic, or ascorbicacid, or quaternary ammonium salts with organic esters of sulfuric,hydrohalic, or aromatic sulfonic acids, such as methyl chloride, methylbromide, ethyl chloride, propyl chloride, butyl chloride, isobutylchloride, benzylchloride, benzyl bromide, phenethyl bromide,naphthymethyl chloride, dimethyl sulfate, methyl benzenesulfonate, ethyltoluenesulfonate, ethylene chlorohydrin, propylene chlorobydrin, allylbromide, methylallyl bromide or crotyl bromide esters.

The compositions described herein include a therapeutically effectiveamount of drug or pharmaceutically acceptable salt(s) thereof.Generally, the amount of drug is from about 0.1% to about 50%, includingfrom about 1% to about 20%, such as from about 1% to about 10% byweight, such as about 1, about 2, about 3, about 4, about 5, about 6,about 7, about 8, about 9 or about 10% by weight, based on the total dryweight of the polymer matrix. In specific embodiments, the polymermatrix comprises about 3, about 4, about 5, about 6, or about 7% byweight clonidine, based on the total dry weight of the polymer matrix.

In accordance with any of the embodiments described herein, thecomposition may include at least an amount of drug (such as clondine) oran equivalent amount of a pharmaceutically acceptable salt thereof for a1 day product, and at least a proportionate amount for a 7 day product.For example, clonidine currently is typically administered at doses ofabout 0.1, 0.2 or 0.3 mg/day in the Catapres-TTS® transdermal patch.(The Catapres-TTS® product is a multi-layer product comprising anadhesive layer, a rate control membrane, and a drug reservoir layer, inaddition to a backing layer and release liner. The drug reservoir layeris an adhesive formulation of clonidine, mineral oil, polyisobutyleneand colloidal silicone dioxide.)

Acrylic Polymers

As noted above, in some embodiments the polymer matrix comprises one ormore acrylic polymers, such as one or more pressure-sensitive adhesiveacrylic polymers. Acrylic polymers suitable for use in polymer matrixcompositions are known.

In accordance with specific embodiments, the polymer matrix comprisesone or more non-acid functional acrylic polymers. Non acid-functionalacrylic polymers include those formed from acrylic esters copolymerizedwith other monomers that do not include acid-functional groups. Nonacid-functional acrylic polymers include homopolymers, copolymers,terpolymers, etc., of acrylic acids and esters. As used herein,“non-acid functional acrylic polymer” includes polymers that includemonomers that have one or more amide groups.

Suitable acrylic polymers can be obtained commercially or bypolymerizing or copolymerizing suitable monomers such as acrylicmonomers and other polymerizable monomers. Acrylate monomers which canbe used include acrylic acid, methacrylic acid, butyl acrylate, butylmethacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate,2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate,2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decylmethacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate,and tridecyl methacrylate. In specific embodiments, the nonacid-functional acrylic polymer includes methacrylate monomers and2-ethylhexyl acrylate monomers. In other specific embodiments the nonacid-functional acrylic polymer includes methacrylate monomers,2-ethylhexyl acrylate monomers, and amide-group containing monomers.

In some embodiments, the non-acid functional acrylic polymer componentof the polymer matrix consists of a single non-acid functional acrylicpolymer. In other embodiments, the non-acid functional acrylic polymercomponent of the polymer matrix comprises a blend of a first at non-acid-functional acrylic polymer and a second non-acid functional acrylicpolymer, and optionally includes additional (e.g., a third or more)non-acid functional acrylic polymers.

When the acrylic polymer component includes more than one nonacid-functional acrylic polymer, the polymers can be present in anyratio that results in a product with satisfactory physical andpharmacokinetic properties. For example, the acrylic polymer componentcan include from 0-100% of a first non acid-functional acrylic polymerand from 100-0% of a second non acid-functional acrylic polymer, basedon the total dry weight of the acrylic component, including about 10 toabout 90%, about 15 to about 85%, about 20 to about 80%, about 25 toabout 75%, about 33 to about 66%, and about 50% of the first nonacid-functional acrylic polymer, and the balance being the second (orthird, etc.) non acid-functional acrylic polymer(s).

Suitable acrylic polymers which are commercially available include thosesold by Henkel (Dusseldorf, Germany), under the Duro-Take brand such asDuro-Tak 87-900A, Duro-Tak 87-9088, Duro-Tak 87-4098, or Duro-Tak87-9900, and those sold by Monsanto (St. Louis, Mo.) under Gelva®Multipolymer Solution brand, such as Gelva 3087 and Gelva-3235.

In some embodiments, the polymer matrix includes one or more acrylicpolymers that includes functional groups. Acrylic-based polymers havingfunctional groups are copolymers or terpolymers which contain, inaddition to the nonfunctional monomer units described above, furthermonomer units having free functional groups. The monomers can bemonofunctional or polyfunctional. These functional groups includecarboxyl groups, hydroxy groups, amino groups, amido groups, epoxygroups, etc. Functional monomers that are copolymerizable alkylacrylates or methacrylates include acrylic acid, methacrylic acid,maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropylacrylate, acrylamide, dimethyl acrylamide, acrylonitrile,dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate,tert-butylaminoethyl acrylate, tert-butylaminoethyl methacrylate,methoxyethyl acrylate and methoxyethyl methacrylate and other monomershaving at least one unsaturated double bond which participates incopolymerization reaction in one molecule and a functional group on itsside chain such as a carboxyl group, a hydroxyl group, a sulfoxyl group,an amino group, an amino group and an alkoxyl, etc. Further examplesinclude monomers with at least one of the following moieties: alkylene,hydroxy-substituted alkylene, carboxylic acid-substituted alkylene,vynylalkanoate, vinylpyrrolidone, vinylpyridine, vinylpirazine,vinylpyrrole, vinylimidazole, vinylcaprolactam, vinyloxazole,vyinlacate, vinylpropionate and vinylmorpholine. Exemplary carboxylfunctional monomers include acrylic acid, methacrylic acid, itaconicacid, maleic acid, and crotonic acid. Exemplary hydroxy functionalmonomers include 2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylate,hydroxymethyl acrylate, hydroxymethyl methacrylate, hydroxyethylacrylate, hydroxyethyl methacrylate, hydroxypropyl acrylate,hydroxypropyl methacrylate, hydroxybutyl acrylate, hydroxybutylmethacrylate, hydroxyamyl acrylate, hydroxyamyl methacrylate,hydroxyhexyl acrylate, hydroxyhexyl methacrylate. The functionalmonomers may be present in any amount, such as from about of 0.1 to 50%by weight, based on the dry weight of the polymer, including about of0.1 to 20% by weight, 0.1 to 15% by weight, 0.1 to 12% by weight, 0.1 to10% by weight, and 0.1 to 8% by weight, based on the dry weight of thepolymer.

Thus, the polymer matrix may include one or more non-acid functionalacrylic polymers and, optionally, one or more functional acrylicpolymers. When the acrylic polymer component includes both functionaland non-acid functional acrylic polymers, the polymers can be present inany ratio that results in a product with satisfactory physical andpharmacokinetic properties. For example, the acrylic polymer componentcan include from 0-100% of non-acid functional acrylic polymer(s) andfrom 100-0% of functional acrylic polymer(s), based on the total dryweight of the acrylic component, including about 10 to about 90%, about15-about 85%, about 20 to about 80%, about 25 to about 75%, about 33 toabout 66%, and about 50% of non acid-functional acrylic polymer(s), andthe balance being the functional acrylic polymer(s).

Other suitable acrylic polymers in addition to those mentioned above areknown in the art. See, e.g., the non acid-functional acrylic polymersdescribed in Satas, “Acrylic Adhesives, HANDBOOK OF PRESSURE-SENSITIVEADHESIVE TECHNOLOGY, 2nd ed. pp. 396-456 (D. Satas, ed.), Van NostrandReinhold, N. Y. (1989); “Acrylic and Methacrylic Ester Polymers,”POLYMER SCIENCE AND ENGINEERING, Vol. 1, 2nd ed., pp 234-268, John Wiley& Sons, (1984).

Polyisobutylene Polymers

As noted above, in some embodiments the polymer matrix comprises one ormore polyisobutylene polymers. Polyisobutylene polymers suitable for usein polymer matrix compositions are known, and include those sold by BASFunder the Oppanol® brand, such as Oppanol® B11. In some embodiments, thepolymer matrix comprises two or more polyisobutylene polymers ofdifferent molecular weights. In accordance with these embodiments, therelative amounts of polyisobutylene polymers can be selected andtailored to produce a product with satisfactory physical andpharmacokinetic properties.

SIS Block Copolymers

As noted above, in some embodiments the polymer matrix comprises one ormore styrene-isoprene-styrene block copolymers. Styrene-isoprene-styreneblock copolymers for use in polymer matrix compositions are known, suchas those sold by Kraton under the Kraton® brand, such as Kraton® D111KT.

As noted above, in some embodiments, the polymer matrices of thecompositions described herein consist essentially of the drug orpharmaceutically acceptable salt(s) thereof and one or more of thepolymer(s) described above, although such compositions may include othernon-polymer components that do not degrade the physical and/orpharmacokinetic properties of the compositions to pharmaceuticallyunacceptable levels, such as one or more penetration enhancers, asdiscussed in more detail below. Further, as noted above, in someembodiments, the polymer matrices are free of or substantially free ofsilicone polymers.

Penetration Enhancers

As noted above, in some embodiments, the polymer matrices of thecompositions described herein further comprise one or more penetrationenhancers. A “penetration enhancer” is an agent known to accelerate thedelivery of the drug through the skin. These agents also have beenreferred to as accelerants, adjuvants, and sorption promoters, and arecollectively referred to herein as “enhancers.” This class of agentsincludes those with diverse mechanisms of action, including those whichhave the function of improving percutaneous absorption, for example, bychanging the ability of the stratum corneum to retain moisture,softening the skin, improving the skin's permeability, acting aspenetration assistants or hair-follicle openers or changing the state ofthe skin including the boundary layer. In specific embodiments theenhancer(s) serve to both enhance penetration of the drug through thestratum corneum and retain the drug at a site local to administration.

Illustrative penetration enhancers include but are not limited topolyhydric alcohols such as dipropylene glycol, propylene glycol, andpolyethylene glycol; oils such as olive oil, squalene, and lanolin;fatty ethers such as cetyl ether and oleyl ether; fatty acid esters suchas isopropyl myristate; urea and urea derivatives such as allantoinwhich affect the ability of keratin to retain moisture; polar solventssuch as dimethyidecylphosphoxide, methyloctylsulfoxide,dimethyllaurylamide, dodecylpyrrolidone, isosorbitol, dimethylacetonide,dimethylsulfoxide, decylmethylsulfoxide, and dimethylformamide whichaffect keratin permeability; salicylic acid which softens the keratin;amino acids which are penetration assistants; benzyl nicotinate which isa hair follicle opener; and higher molecular weight aliphaticsurfactants such as lauryl sulfate salts which change the surface stateof the skin and drugs administered. Other agents include oleic andlinoleic acids, ascorbic acid, panthenol, butylated hydroxytoluene,tocopherol, tocopheryl acetate, tocopheryl linoleate, propyl oleate, andisopropyl palmitate. In some embodiments, combinations of two or moreenhancers are used.

Generally speaking, the polymer matrices may include drug in an amountfrom about 1% to about 50%, including from about 1% to about 10%, suchas from about 1% to about 5%, including about 1%, about 2%, about 3%,about 4% about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%by weight, based on the total dry weight of the polymer matrix.

Generally speaking, the acrylic polymer(s) may be present in a rangefrom about 50% to about 95%, including from about 75% to about 95%, suchas from about 85% to about 95%, including from about 87% to about 91%,including about 88%, about 89%, and about 90%, by weight, based on thetotal dry weight of the polymer matrix.

Generally speaking, the polyisobutylene polymer(s) may be present in arange from about 1% to about 10%, including from about 2% to about 7%,including from about 3% to about 5%, including about 2%, about 2.5%,about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about6%, about 6.5%, and about 7%, by weight, based on the total dry weightof the polymer matrix.

Generally speaking, the styrene-isoprene-styrene block copolymer(s) maybe present in a range from about 0.1% to about 10%, including from about1% to about 5%, including from about 1% to about 2%, including about1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%,and about 5%, by weight, based on the total dry weight of the polymermatrix.

Generally speaking, the penetration enhancer(s), if present, may bepresent in an amount from about 0.1% to about 10%, such as from about0.1% to about 5%, including about 0.2%, about 0.4%, about 0.6%, about0.8%, about 1.0%, about 2%, about 3%, about 4%, about 5%, about 6%,about 7%, about 8%, about 9%, or about 10%, by weight, based on thetotal dry weight of the polymer matrix. In embodiments using more thanone enhancer, each may be present in any amount described herein (e.g.,from about 0.1% to about 10%) or the total amount of enhancers may bewithin the amounts described herein (about 0.1% to about 10%).

While not wanting to be bound by any theory it is believed that thepolymer blends described herein balance competing goals and propertiesof drug solubility, drug delivery and physical properties, such as wearproperties. For example, while the acrylic polymers exhibit goodsolubility for amine-functional drugs, they generally have poorlong-term wear properties. While silicone polymers have been used toimprove the wear properties of acrylic-containing polymer matrices,silicone may interact with amine-functional drugs, leading to high peelforce problems. The present inventors surprisingly found thatmulti-polymer matrix compositions comprising acrylic polymer(s),polyisobutylene polymer(s) and styrene-isoprene-styrene blockcopolymer(s) achieve desired drug delivery of amine-functional drugswhile also exhibiting satisfactory storage and wear properties, andwithout suffering from high peel force problems. Thus, while not wantingto be bound by any theory, the present inventors believe that thepolyisobutylene polymer(s) and styrene-isoprene-styrene blockcopolymer(s) improve the physical properties of the polymer matrix andimprove the stability of the matrix composition both during themanufacturing process, and during storage and use.

Additionally, the multi-polymer matrix compositions described hereinachieve desired drug delivery of amine-functional drugs, includingrelatively high drug flux and sustained drug delivery (includingdelivery over a period of 7 days), with relatively low drug loading.

Further, the use of two or more acrylic polymers in accordance with someembodiments described herein permits even greater control over theproperties of the polymer matrix and the resulting pharmacokinetics ofdrug delivery. For example, two or more acrylic polymers may be selectedwith different solubilities for the specific drug(s) being formulatedand/or with different physical properties (e.g., tack and wear).

Overall, the compositions described herein achieve effective, sustaineddrug delivery with relatively low drug loading, and exhibit goodphysical properties, including storage stability and wear properties.

Backing Layer

The compositions in flexible, finite form comprise a polymer matrix,such as described above, and a backing layer. The backing layer isimpermeable to the drug (e.g., impermeable to the amphetamine) and isadjacent one face of the polymer matrix. The backing layer protects thepolymer matrix from the environment and prevents loss of the drug and/orrelease of other components to the environment during use. The backinglayer may be any backing layer known in the art for transdermal drugdelivery systems.

Release Linter

The compositions in flexible, finite form may further comprise a releaseliner, typically located adjacent the opposite face of the system ascompared to the backing layer. When present, the release liner isremoved from the system prior to use to expose the polymer matrix layerprior to topical application. Materials suitable for use as releaseliners are well-known known in the art and commercially available, suchas polyester release liners, including coated polyester release liners.

Methods of Manufacture

The compositions described herein can be prepared by methods known inthe art. As one step, the polymer matrices described herein can beprepared by methods known in the art, such as blending (mixing) thepolymer components in powder or liquid form with an appropriate amountof drug in the presence of an appropriate solvent, such as a volatileorganic solvent, optionally with other excipients. To form a finalproduct, the drug/polymer/solvent mixture may be cast onto a releaseliner (optionally, at ambient temperature and pressure) followed byevaporation of the volatile solvent(s), for example, at roomtemperature, slightly elevated temperature, or by a heating/drying step,to form the drug-containing polymer matrix on a release liner. A backinglayer may be applied to form a final product.

An exemplary general method for preparing a unit final product of acomposition as described herein in a flexible, finite form, is asfollows:

1. Appropriate amounts of one or more polymers, solvent(s) and/orco-solvent(s), and optional excipient(s) are combined and thoroughlymixed together in a vessel.

2. The drug is added to the mixture and agitation is carried out untilthe drug is uniformly mixed therein.

3. The composition is transferred to a coating operation where it iscoated onto a release liner at a controlled specified thickness. Solventis removed from the coated composition, such as by passing thecomposition through an oven in order to drive off all volatileprocessing solvents.

4. The composition is provided with a backing layer, and optionallywound into rolls for storage until final processing.

5. Appropriate size and shape delivery systems are prepared, such as bydie-cutting from the roll material, and then packaged into pouches.

The order of steps, the amount of the ingredients, and the amount andtime of agitation or mixing may be important process variables whichwill depend on the specific polymers, active agents, solvents and/orcosolvents, and optional excipients used in the composition, but thesefactors can be adjusted by those skilled in the art. The order in whicheach method step is performed can be changed if needed withoutdetracting from the invention.

The polymer matrix composition may be applied at a coat weight typicalof those used in the art. In some embodiments, the polymer matrixcomposition is applied at a coat weight of about 10 mg/cm². In someembodiments, the polymer matrix composition is applied at a coat weightof about 12.5 mg/cm². In some embodiments, the polymer matrixcomposition is applied at a coat weight of about 15 mg/cm².

Polymer matrix compositions comprising acrylic polymer(s),polyisobutylene polymer(s) and styrene-isoprene-styrene blockcopolymer(s) also can be made by the following methods, which addressthe difficulties that can be encountered when blending acrylicpolymer(s), and rubber polymers (such as polyisobutylene polymer(s) andstyrene-isoprene-styrene block copolymer(s)) which generally do notblend well with each other. If any polymer component comprises anysolvent, such as may result from the manufacturing process or as may bepresent in the polymer component as provided by the manufacturer/vendor,the solvent is removed. This can be done by any means known in the art,such as by drawing down a laminate of each polymer component on arelease liner and drying the laminate, such as by exposing the laminateto elevated temperatures to evaporate any solvent present, such as byplacing the laminate in an oven at an appropriate temperature and for anappropriate time. For the method, a solvent is selected that exhibitsmiscibility for the drug and polymer components, such as a solvent thatwill dissolve the drug and polymer components. For example, when thedrug is clonidine, the solvent may be toluene. The polymer componentsare added to the solvent at an appropriate solids content for formingthe matrix, e.g., to achieve a viscosity that is conducive to forming astable blend. A typical solids content is between 30% and 50%. After thepolymer components are blended, the drug is added and blended. Then, themanufacturing process can continue as outlined above, e.g., by coatingthe composition onto a release liner, providing a backing layer, andforming the final product.

In accordance with any of the embodiments of compositions describedherein, the size of the final product is, in some embodiments, in therange of from about 2 cm² to about 100 cm², including 5 cm², 10 cm², 20cm², 25 cm², 30 cm², 40 cm², 50 cm², 60 cm², 70 cm², 75 cm², 80 cm², and90 cm².

Methods of Use

The compositions described herein are useful in methods for thetransdermal delivery of any drug, and are particularly suited foramine-functional drugs. Thus, the compositions described herein can beused in the treatment of any condition that for which anamine-functional drug is prescribed. In the case of clonidine, forexample, compositions described herein comprising clonidine are usefulfor the treatment of hypertension and other cardiovascular conditions.In such embodiments, a composition comprising a therapeuticallyeffective amount of clonidine is topically applied to a subject in needthereof.

In some embodiments, the compositions achieve transdermal delivery ofdrug over a period of time of at least about 8 hours, including a periodof time of at least about 8 hours to at least about 12 hours, at leastabout 24 hours, or longer. In other embodiments, the compositionsachieve transdermal delivery of drug over a longer period of time, suchas over a period of at least about 2 days, at least about 3 days, atleast about 4 days, at least about 5 days, at least about 6 days, atleast about 7 days, or longer.

The compositions described herein achieve a transdermal flux of drug(and/or one or more pharmaceutically acceptable salt(s) thereof) that issufficient to have a therapeutic effect. As used herein, “flux” (alsocalled “permeation rate”) is defined as the absorption of a drug throughskin or mucosal tissue, and is described by Fick's first law ofdiffusion:

J=−D(dCm/dx)

where J is the flux in g/cm²/sec, D is the diffusion coefficient of thedrug through the skin or mucosa in cm²/sec and dCm/dx is theconcentration gradient of the drug across the skin or mucosa.

In clonidine embodiments, the compositions described herein may achievea transdermal flux of clonidine sufficient to deliver at least 0.1 mg,at least 0.2 mg, or at least 0.3 mg/day over the period of application,e.g., over a period of time of at about 24 hours (for a 1 day product)or over a period of time of about 7 days (for a 7 day product).

The following specific examples arc included as illustrative of thecompositions described herein. These example are in no way intended tolimit the scope of the invention. Other aspects of the invention will beapparent to those skilled in the art to which the invention pertains.

EXAMPLE 1

Multi-polymer matrix compositions as described herein are prepared asdescribed above using toluene as the solvent during the manufacturingprocess.

TABLE 1 1 2 3 4 5 6 7 8 9 10 RN RN RN RN RN RN RN RN RN RN Comp. 018-018- 018- 018- 018- 018- 018- 018- 018- 018- Sample 168-3 169-2 180-1180-2 180-3 180-5 180-6 181-2 181-4 181-6 Clonidine 6 4 3 5 7 4 6 5 4 4DT 87-900A 25 — — — — — — — — — DT 87-9088 65 30 30 30 29 — — 30 — 20 DT87-4098 — — — — — 30 29 — 30 50 DT 87-9900 — 60 61 59 58 60 59 59 60 20Oppanol B11 3.0 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 Kraton SIS 1.0 1.51.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 Coat Weight 10 10 10 10 10 10 10 15 1510 (mg/cm²)

Drug flux from Composition 1 over 24 hours was assessed and compared todrug flux from the commercial Catapres-TTS® 3 clonidine product (7.5 mgclonidine in a 10.5 cm² patch). Results are shown in FIG. 1. As the datademonstrate, Composition 1 achieved higher drug flux than the commercialproduct, even though it includes less drug per unit area (0.6 mg/cm² vs.0.7 mg/cm²).

Drug flux from Compositions 2, 6 and 7 over 7 days was assessed andcompared to drug flux from the commercial Catapres-TTS® 3 clonidineproduct (7.5 mg clonidine in a 10.5 cm² patch). Results are shown inFIG. 2, where the top three line set forth data from Compositions 2, 6,and 7, and the bottom line sets forth data from Catapres-TTS® 3. As thedata demonstrate, Compositions 2, 6 and 7, achieved higher drug fluxthan the commercial product, even though they include less drug per unitarea (0.4 mg/cm² or 0.6 mg/cm² vs. 0.7 mg/cm²).

EXAMPLE 2

Peel properties of the compositions of Example 1 were assessed bymeasuring the peel force needed to remove the polymer matrix from astainless steel plate. The results are shown in Table 2.

TABLE 2 Peel from Stainless Steel Plate Lot # High Average St. Dev(Avg.) RN 018-180-1 171.2 144.0 23.0 RN 018-180-2 170.3 212.0 6.38 RN018-180-3 252.4 22.7 RN 018-180-5 334.2 311.9 12.3 RN 018-180-6 334.7296.2 5.15 RN 018-181-2 339.5 286.0 8.96 RN 018-181-4 378.8 343.8 14.2RN 018-181-6 300.6 279.4 9.07

The results show that the peel values vary with the composition,indicating that the different acrylic polymers and relative amountsthereof, as well as the amount of drug and coat weight, can impact peelvalues. The results therefore confirm that these properties can beselected and controlled to achieve desired physical properties.

What is claimed is:
 1. A multi-polymer composition for the transdermaldelivery of an amine-functional drug in the form of a flexible finitesystem for topical application, comprising a polymer matrix comprising(i) a therapeutically effective amount of an amine-functional drug; (ii)an acrylic polymer; (iii) a polyisobutylene polymer, and (iv) astyrene-isoprene-styrene block copolymer.
 2. The composition of claim 1,wherein the amine-functional drug comprises clonidine.
 3. Thecomposition of claim 1, wherein the polymer matrix comprises two or moreacrylic polymers.
 4. The composition of claim 1, wherein the polymermatrix comprises a non acid-functional acrylic polymer.
 5. Thecomposition of claim 1, wherein the polymer matrix comprises about 1% to10% w/w clonidine.
 6. The composition of claim 1, wherein the polymermatrix comprises about 85% to 95% w/w acrylic polymer.
 7. Thecomposition of claim 1, wherein the polymer matrix comprises about 3% to5% w/w polyisobutylene polymer.
 8. The composition of claim 1, whereinthe polymer matrix comprises about 1% to 2% w/w styrene-isoprene-styreneblock copolymer.
 9. The composition of claim 1, wherein the polymermatrix has a coat weight of about 10 to 15 mg/cm².
 10. The compositionof claim 1, wherein the system achieves delivery of the amine-functionaldrug over a period of time of about 24 hours.
 11. The composition ofclaim 1, wherein the system achieves delivery of the amine-functionaldrug over a period of time of about 7 days.
 12. The composition of claim1, further comprising a backing layer.
 13. The composition of claim 1,further comprising a release liner.
 14. A method for the transdermaldelivery of an amine-functional drug, comprising topically applying acomposition according to claim 1 to the skin or mucosa of a subject inneed thereof.
 15. A method for the manufacture of a composition asclaimed in claim 13, comprising: optionally, drying one or more of anacrylic polymer, a polyisobutylene polymer, and astyrene-isoprene-styrene block copolymer to remove any solvent;dissolving an acrylic polymer, a polyisobutylene polymer, and astyrene-isoprene-styrene block copolymer in a solvent miscible with theamine-functional drug and polymer components and mixing to form apolymer blend; adding the amine-functional drug to the polymer blend andmixing to form a polymer matrix; applying the polymer matrix to arelease liner; removing solvent from the polymer matrix; and providingthe polymer matrix with a backing layer.
 16. The method of claim 15,wherein the amine-functional drug is clonidine and the solvent istoluene.